FOR 2290:  Understanding Intramembrane Proteolysis

• Subject Area: Biology
• Term: from 2015 to 2023
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 263531414

Intramembrane proteases cleave their substrates within or adjacent to membrane-spanning regions. Thereby, these unusual proteases affect a wide range of important biological functions and are implicated in several severe diseases including Alzheimer´s diseases (AD), the most common neurodegenerative disease. The great importance of research on intramembrane proteolysis is reflected by a recent special issue on Intramembrane Proteases in BBA Biomembranes (Vol. 1828, 2013) and a dedicated Gordon Research Conference on “Regulated Proteolysis of Cell Surface Proteins - Sheddases and Intramembrane-Cleaving Proteases: From Basic Research to Clinical Applications” (Ventura, March 30 to April 4, 2014). However, despite of more than a decade of research, we neither know the full repertoire of substrates and their functions nor do we understand the molecular properties that qualify a substrate as such. It is thus unclear what distinguishes substrates from non-substrates in structural terms. On the one hand, the transmembrane domains of known substrates exhibit a tremendous diversity of primary structures. On the other hand, only a fraction of single-span proteins are known as substrates and point mutations within them can strongly interfere with their proteolysis. This puzzling discrepancy between seemingly promiscuous and clearly sequence-specific processing of substrates indicates that their transmembrane domains share structural features that allow for specific recognition and cleavage by a given protease. The research group assembled in this proposal is uniquely qualified to solve the open question of how specificity of intramembrane proteolysis is achieved. Some of its members have a long and successful history in intramembrane proteolysis research and were among those who started the field while others have outstanding expertise in the structure/function analysis of transmembrane helices. Together, they will apply a cross-disciplinary approach to i) identify novel substrates for different types of intramembrane proteases and ii) explore for some paradigmatic cases how proteolysis is related to substrate/enzyme interaction and to the structure and conformational flexibility of the substrate transmembrane helices. This entails investigating the effect of disease-associated substrate mutations. Since intramembrane proteases are considered as relevant drug targets for various diseases a deep knowledge of their cleavage mechanism is crucially required in order to develop save and effective disease-modifying intramembrane protease inhibitors and/or modulators.

• DFG Programme: Research Units

Projects

• Coordination Funds (Applicant Langosch, Dieter )
• Dynamics of Substrate-Protease Interactions (Applicants Simmel, Friedrich ;  Zacharias, Martin )
• Functional role of transmembrane domain interactions and intramembrane cleavage of microglial innate immunity receptors (Applicant Haass, Christian )
• Investigation of Molecular Dynamics of Substrate Transmembrane alpha-Helices by Solution and Solid-State NMR Spectroscopy (Applicants Huster, Ph.D., Daniel ;  Muhle-Goll, Claudia )
• Mechanistic characterization of substrate recognition by gamma-secretase (Applicant Lichtenthaler, Stefan )
• Proteomic platform (Applicant Lichtenthaler, Stefan )
• Substrate recognition and binding by Signal Peptide Peptidase-like 2 (SPPL2) family (Applicant Fluhrer, Regina )
• Substrate recognition and cleavage by the mitochondrial rhomboid protease PARL (Applicant Lemberg, Marius )
• Substrate recruitment and cleavage by γ-secretase (Applicant Steiner, Harald )
• Substrate Transmembrane Helices: Conformational Flexibility and Recognition by an Enzyme (Applicant Langosch, Dieter )

• Spokesperson: Professor Dr. Dieter Langosch